Inflammation refers to a pathological state of abscess formed by infection from external sources of infection (bacteria, fungi, viruses, various types of allergens, etc.). Specifically, when external microbes infect a specific tissue and proliferate, leukocytes of the living organism recognize and actively attack the external microbes. Dead leukocytes caused by the above process are accumulated in the tissue infected by the microbes, and cell debris of the infected microbes killed by the leukocytes fuses with the infected tissue, which results in formation of abscesses. Treatment of an abscess caused by inflammation can be stimulated by an anti-inflammatory action, which stimulates the treatment of inflammation by suppressing proliferation of infected microbes using an antimicrobial agent or by activating macrophages ingesting foreign substances accumulated in the abscess to accelerate a function of the macrophages digesting and excreting the foreign substances.
Generally, the inflammatory response is a process of a defense mechanism in a living organism to repair and regenerate from damage caused by an invasion causing an organic change in cells or tissues of the living organism, and in this process, various tissue cells and immune cells of local blood vessels and body fluids are used. Normally, inflammatory response induced by external infectious microbes is a defense system for protecting a living organism, but when an abnormal excessive inflammatory response is induced, various diseases are caused, which are called inflammatory diseases. The inflammatory diseases are life-threatening diseases caused when various inflammation-mediated substances secreted from target cells activated by external stimuli induce amplification and sustainment of inflammation, and include acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, sepsis, septic shock, acute respiratory distress syndrome, multiple organ failure, and chronic obstructive pulmonary disease.
The occurrence of various inflammatory diseases is associated with activation of macrophages and excessive production of inflammatory factors caused thereby, and as a representative inflammatory factor, IL-β, tumor necrosis factor (TNF)-α, or nitrogen oxide (NO) is used.
Lipopolysaccharide (LPSs) of the inflammatory substances for the inflammatory response is a substance for forming a cell surface of Gram-negative bacteria, and interacts with immune cells such as leukocytes and is associated with regulation of inflammatory cytokines.
Particularly, one of the inflammatory diseases, sepsis, refers to the occurrence of systemic inflammatory response syndrome (SIRS) from several microorganisms. Sepsis is caused by the influx of microbes having a symbiotic relationship with the adjacent tissues from the gastrointestinal tract or skin, and partial infections of the genitourinary tract, bile, lung, or gastrointestinal tract can cause blood infections. In addition, such microbes may directly infiltrate into blood by intravenous injection. That is, reactions of the host, which is a human, caused by microbial infection appear in various types of inflammatory responses, for example, high or low fever, chills, tachycardia, tachypnea, etc. Sepsis is a very deadly disease that can develop into severe sepsis, septic shock, or a multiple organ dysfunction syndrome (MODS) in which dysfunctions of the lung, kidney, liver, or circulatory system arise as complications and that can lead to death when causes of the sepsis are not quickly and accurately diagnosed early.
Sepsis can occur in all people infected with microbes. Among such people, sepsis occurs more frequently, particularly, in very young infants, the elderly, or hospitalized patients such as people with weak immune systems, people with scars or wounds caused by traffic accidents, alcoholics or drug addicts, or patients who are receiving treatment with catheters in a hospital.
It is reported that sepsis is a representative incurable disease leading to death at a rate of 20 to 50%, and contributes to severe sepsis for 18 million or more people every year in the world, and has also become a major cause of death of approximately 1,400 people every day, which is 5 to 10 times the rate of colorectal cancer and breast cancer. Every year, 215,000 or more people in the United States, and 135,000 or more people in Europe die because of sepsis, which, along with cancer, is among the top 10 causes of death in the United States. The situation is further complicated by phenomena such as aging, prolonging of life of chronically-ill patients, AIDS, etc., and such phenomena are also expected to increase in Korea.
Sepsis is caused by various microorganisms, for example, also by fungi or viruses, but mostly by bacteria. According to the blood culture for 30 to 60% of sepsis patients and 60 to 80% of septic shock patients, gram-negative bacteria are shown in approximately two-thirds of the patients, and gram-positive bacteria are only shown in 10 to 20% of the patients. Recently, there is a tendency of an increase in gram-positive bacteria over gram-negative bacteria as a major cause of sepsis.
It has been disclosed in recent research that septic mortality closely relates to the inability to regulate an inflammatory reaction resulting from intrinsic immune system disorders in early sepsis. In addition, sepsis is accompanied by excessive apoptosis of lymphocytes, and accordingly, multi-organ failure occurs. The level of cytokines is significantly changed, and pro-inflammatory cytokines, that is, TNF-α and IL-β, are significantly increased. Therefore, microbicidal action, prevention of imbalance of cytokines, or inhibition of the apoptosis of lymphocytes or cell death should be targeted in the treatment of sepsis.
Phospholipase C (PLC) is an enzyme for hydrolyzing phospholipids by cleaving a phosphate group. Phosphatidylinositol-specific PLC (PI-PLC) is one of the information-transforming phospholipases catalyzing the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) in a signal transduction pathway within phospholipids of a cell membrane to produce second messengers (inositol-1,4,5-trisphosphate and 1,2-diacylglycerol). PLC plays an important role in regulation of leukocyte activation by various extracellular stimuli, and the increase in activation of intracellular calcium and protein kinase C is associated with intracellular signal transduction, which includes activation of phospholipase A2, phospholipase D, and mitogen-activated protein kinase (MAPK). In addition, PLC-involved signal transduction regulates cellular responses including production, secretion, and maintenance of superoxides.
It is known that PLC is very important as a cell signaling substance, but its pathophysiological role has not yet been clearly identified. Accordingly, the inventors of the present invention developed m-3M3FBS, which is a direct regulator of PLC, through screening of small molecule libraries, and confirmed a pharmaceutical role and effect of m-3M3FBS in inflammatory diseases and infectious diseases, thereby inventing a pharmaceutical composition for treating or preventing and health supplements for improving or preventing inflammatory diseases or infectious diseases.